Interest in 5-HT7 receptors derives mainly from the possibility that they can play a relevant role in normal or impaired memory. Numerous studies have found evidence of the presence of 5-HT7 receptors in cognitive pathways within hippocampal formation (HF) and the frontal cortex. It is known that 5-HT7 receptors appear to decline in the raphe complex during aging or Alzheimer's disease (AD). The evidence for the involvement of 5-HT7 receptors in mnemonic mechanisms was also confirmed by findings showing that the potential selective 5-HT7 receptor agonist AS 19 enhanced memory consolidation, attenuated mRNA receptors expression, and the facilitatory memory effect was reversed by SB-269970 (5-HT7 receptor antagonist). Understanding the role of 5-HT7 receptors in cognitive processes, including learning and memory, is limited by the lack of highly selective agonists. The central hypothesis of the proposed project is that the agonist ligands of arylpiperazine, thiopyridine and 2-anilinoimidazoline analogs bind in a similar manner upon interaction with 5-HT7 receptors and utilize some common ethylamine side-chain conformation required for agonist activity at the receptor. The major goal of the proposed research is to exploit a series of conformationally restricted pyridine and thiopyridine analogs, and to use them as templates for the design and development of potent and highly selective 5-HT7 receptor agonists. These templates are derived from a comparable analysis of four major classes of selective and nonselective 5-HT7 receptor agonists: arylpiperazines, aminotetralins/chromans, thiopyridines, and 2-anilinoimidazolines. The nature and position of substituents in the proposed templates can also provide us with a diversity of new 5-HT7 receptor agonists. The specific aims of this application are as follows: (i) prepare a series of conformationally restricted pyridie and thiopyridine analogs as potential agonists based on the templates containing common structural elements; (ii) determine their binding profile initially at 5-HT7 receptors and then stuy their affinity at 5-HT1A, 5-HT2A, D2L, 1, and 2 adrenoceptors to determine selectivity; (iii) determine the intrinsic activity of the proposed structures at 5-HT7 receptors, except for those that will have no affinity at 5-HT7 receptors; (iv) utilize the proposed templates and obtained pharmacological results to identify key structural elements essential for selectivity and agonist activity for 5-HT7 receptors. The findings of the proposed studies will serve as preliminary data for a further long-term project. The aim of the project will include: (i) development of the structure-affinity relationships (SAFIR) and structure-activity relationships (SAR) of the 5-HT7 receptor agonists, (ii) clarification of the function of 5-HT7 receptors and their agonists in the etiology of memory disorders, and (iii) design and development of potent agents that may find therapeutic application for the treatment of dysfunctional memory in aged-related decline and AD.